Locus control region

Source: Wikipedia, the free encyclopedia.

A locus control region (LCR) is a long-range

silencers. The LCR functions by recruiting chromatin-modifying, coactivator, and transcription complexes.[2] Its sequence is conserved in many vertebrates, and conservation of specific sites may suggest importance in function.[2] It has been compared to a super-enhancer as both perform long-range cis regulation via recruitment of the transcription complex.[3]

History

The β-globin LCR was identified over 20 years ago in studies of

transgenic mice. These studies determined that the LCR was required for normal regulation of beta-globin gene expression.[4] Evidence of the presence of this additional regulatory element came from a group of patients that lacked a 20 kb region upstream of the β-globin cluster that was vital for expression of any of the β-globin genes. Even though all of the genes themselves and the other regulatory elements were intact, without this domain, none of the genes in the β-globin cluster were expressed.[5]

Examples

See also: Human β-globin locus

Although the name implies that the LCR is limited to a single region, this implication only applies to the β-globin LCR (HBB-LCR). Other studies have found that a single LCR can be distributed in multiple areas around and inside the genes it controls. The β-globin LCR in mice and humans is found 6–22 kb upstream of the first globin gene (epsilon). It controls the following genes:[1][2]

  • HBE1, hemoglobin subunit epsilon (embryonic)
  • HBG2, hemoglobin subunit gamma-2 (fetal)
  • HBG1, hemoglobin subunit gamma-1 (fetal)
  • HBD, hemoglobin subunit delta (adult)
  • HBB
    , hemoglobin subunit beta (adult)

There is an

teleost fishes including zebrafish.[8]

As of 2002, there are 21 LCR areas known in human.[1] As of 2019, 11 human LCRs are recorded in the NCBI database.[9]

Proposed models of LCR function

Although studies have been conducted to attempt to identify a model of how the LCR functions, evidence for the following models is not strongly supported or precluded.[1]

Looping model

Transcription factors bind to hypersensitive site cores and cause the LCR to form a loop that can interact with the promoter of the gene it regulates.[1]

Tracking model

Transcription factors bind to the LCR to form a complex. The complex moves along the DNA helix until it can bind to the promoter of the gene it regulates. Once bound, the transcriptional apparatus increases gene expression.[1]

Facilitated tracking model

This hypothesis combines the looping and tracking models, suggesting that the transcription factors bind to the LCR to form a loop, which then seeks and binds to the promoter of the gene it regulates.[1]

Linking model

Transcription factors bind to DNA from the LCR to the promoter in an orderly fashion using non-DNA-binding proteins and chromatin modifiers. This changes chromatin conformation to expose the transcriptional domain.[1]

Diseases related to the LCR

Studies in transgenic mice have shown that deletion of the β-globin LCR causes the region of chromosome to condense into a heterochromatic state.[1][2] This leads to decreased expression of β-globin genes, which can cause β-thalassemia in humans and mice.

References

  1. ^
    PMID 12384402
    .
  2. ^
    PMID 11895428
    .
  3. PMID 30500078
    .
  4. PMID 17567988
    .
  5. ^ Nussbaum R, McInnes R, Willard H (2016). Thompson &Thompson Genetics in Medicine (Eighth ed.). Philadelphia: Elsevier. p. 200.
  6. PMID 16647849
    .
  7. PMID 20638402
    .
  8. PMID 21971525
    .
  9. ^ "Search: "locus control region"[title] AND "Homo sapiens"[porgn] AND alive[prop]". NCBI Gene. Retrieved 20 August 2019.
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